Synthesis and antifolate properties of 9-alkyl-10-deazaminopterins.
Reformatski condensation of benzyl 2-bromopropionate with 4-carbomethoxybenzaldehyde, followed by dehydration afforded benzyl 2-methyl-p-carbomethoxycinnamate (4a). Hydrogenation over a Pd catalyst gave the hydrocinnamic acid 5a. Conversion to the chloromethyl (6a) and azidomethyl ketone (7a) was followed by hydrogenation to the aminomethyl ketone (8a). Direct N-alkylation by 2,4-diamino-5-nitro-6-chloropyrimidine followed by reductive ring closure in Zn-HOAc and subsequent saponification of the benzoate ester yielded 4-amino-4-deoxy-9-methyl-10-deazapteroic acid (11a). Coupling with diethyl L-glutamate and saponification afforded 9-methyl-10-deazaminopterin (13a). The 9-ethyl analogue (13b) was similarly prepared from benzyl 2-bromobutyrate. The 9-methyl analogue (13a) was 21 times more potent than MTX as an inhibitor of cell growth in L1210 cells. The reason for this enhanced cytotoxicity in L1210 is unclear, since enzyme inhibition and transport parameters were similar to those of MTX. In human Manca leukemia cells growth inhibition was not dramatic and paralleled MTX.
DeGraw
J I
JI
Bio-Organic Chemistry Laboratory, SRI International, Menlo Park, California 94025.
Christie
P H
PH
Kisliuk
R L
RL
Gaumont
Y
Y
Sirotnak
F M
FM
D000630:Aminopterin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D005493:Folic Acid Antagonists; D006801:Humans; D007938:Leukemia / Q000201:enzymology; D007939:Leukemia L1210 / Q000188:drug therapy / Q000201:enzymology; D008727:Methotrexate / Q000494:pharmacology; D015394:Molecular Structure; D014407:Tumor Cells, Cultured
D005493:Folic Acid Antagonists; C062443:9-methyl-10-deazaminopterin; D000630:Aminopterin; D008727:Methotrexate